Over the last years a big effort has been made to understand the molecular mechanisms that dictate tooth development, pathology, and repair [1, 14]. To this contributed the constantly increasing knowledge on genetics, stem cells, and tissue engineering.

Signaling molecules control all steps of odontogenesis by coordinating cell proliferation, differentiation, apoptosis, extracellular matrix synthesis, and mineral deposition. The same molecules are repetitively used during the different stages of odontogenesis and are regulated according to a precise timing mechanism [1, 15–17]. Signals produced at a wrong time lead to inappropriate cell proliferation, differentiation, and apoptosis, thus affecting the overall tooth development and morphology [1].

The territory where teeth will form is defined early, before any obvious sign of tooth development. The earliest marker of the odontogenic territory within the oral epithelium is the transcription factor Pitx2 [18, 19]. Dental fields are also established by morphogenic signals that determine the display and fate of the CNC cells, thus leading to the generation of distinct tooth shapes [20, 21]. For example, ectodysplasin (Eda) molecules are involved in the determination of dental fields size that controls teeth number [22]. In fact, increased Eda signaling leads to supernumerary teeth formation, while Eda deletion often leads to tooth number reduction [1, 22].

Bone morphogenic proteins (BMPs) , Wnts, sonic hedgehog (shh), and fibroblast growth factors (FGFs) regulate the epithelial-mesenchymal interactions during tooth initiation [1, 17]. BMP4 and FGF8 molecules constitute essential early oral epithelial signals that activate tooth specific genes (e.g. Msx1, Msx2, Barx1, Dlx1, Dlx2, Pax9) in the underlying mesenchyme [1, 18, 19, 23], thus controlling tooth patterning (i.e., BMP4 directs incisors shape while FGF8 molars shape) [2, 21].

The specification of the various dental cell-types involves genes with restricted expression patterns during odontogenesis. It has been proposed that the determination of cell fates in teeth occurs via inhibitory interactions between adjacent cells through the Notch signaling pathway [17, 24]. Indeed, previous studies have shown that molecules of the Notch signaling pathway are involved in tooth development and dental cell specification [25–29]. In order to influence developmental decisions, molecules of the Notch signaling pathway must obviously interact with other signaling pathways. Notch-dependent cell fate acquisition between non-equivalent dental precursor cells is influenced by extrinsic signals such as BMP and FGF molecules. BMP and FGF molecules have opposite effects on the expression of Notch receptors and ligands in dental tissues [25, 26, 29], indicating that cell fate choices during odontogenesis are under the concomitant control of the Notch and BMP/FGF signaling pathways. Furthermore, it has been shown that Notch-mediated lateral inhibition has a pivotal role in the establishment of the tooth morphology, as shown in Jagged2 mutant mice where the overall development and structure of their teeth is severely affected [28, 29]. Several genetic findings have shown that Tbx1 plays a significant role for the early determination of epithelial cells to adopt the ameloblast fate. Indeed, hypoplastic incisors that lack enamel are observed in mice lacking the Tbx1 gene [30, 31]. Mesenchyme-derived FGF molecules activate the expression of Tbx1 in dental epithelium [32, 33].

Traumatic injuries and external harmful agents such as bacteria and acids jeopardize tooth integrity. Periodontal disease and caries are mainly responsible for pathologies affecting the dental and alveolar bone tissues. Dental pathologies, combined with age, constitute important factors that can trigger tooth loss [34].

In most cases, the reparative mechanisms following dental and periodontal injuries involve a series of highly conserved processes that share genetic programs that occur throughout embryogenesis [14]. For example, after severe injury or inflammation of the dental pulp (i.e., pulpitis), the dying odontoblasts are replaced by progenitor cells, which differentiate into a new generation of odontoblasts and produce the reparative dentin [14, 35]. Signaling molecules released at the injury sites may attract progenitor cells, thus initiating the healing processes.

The increased knowledge on the reparative events within dental tissues has contributed to the proposal of alternative methods for the treatment of dental pathologies. However, traditional treatments continue to be applied in dental clinics since most of these novel approaches are at the experimental level and not well established yet.

Restorative dentistry has undergone significant advances in recent years [36, 37]. Contemporary techniques to replace partially lost hard tissues consist of direct or indirect tooth-colored restorations (e.g., resin-based composites, porcelain inlays and onlays). The resin-based composites are bonded to the dental tissues through elaborated adhesive materials. While adhesion to enamel is stable over time, adhesion to dentin is weaker and unstable, mainly because of the higher levels of organic matrix of dentin [38]. Therefore, the goal of the adhesive procedures is the widespread infiltration and encapsulation of the demineralized collagen fibrils of dentin with the monomeric resin [37, 39]. Dentin biomodification strategies have as goal to enhance the properties of dentin matrix, thus inducing remarkable resin resistance against degradation that leads to short durability of restorations [39–41].

Endodontic therapy is a procedure implying the removal of contaminated or necrotic dental tissues within the pulp, thus eliminating future tooth contamination. Clinically, vital pulp therapy can be divided into two main groups: indirect and direct pulp capping. Indirect pulp capping is achieved by applying a protective agent on the thin layer of dentin remaining over a nearly exposed pulp, in order to allow the underlying dental pulp to repair [42]. Direct pulp capping necessitates the use of a protective agent directly on the exposed pulp, thus allowing pulp regeneration [43]. In case of large pulp exposure or infection, the coronal pulp has to be removed before direct pulp capping at the tooth root level (i.e., pulpotomy) [44]. This method preserves the vitality of pulp located at the root canal, thus allowing the accomplishment of the root growth [45]. Apexogenesis is another procedure of vital pulp treatment that promotes physiological development and formation of the root using mineral trioxide aggregates [46]. When the whole pulp is damaged or infected is replaced with inorganic materials such as guttapercha after thorough root canal treatment . However, root canal treatment results in the loss of dental pulp vitality. Dental pulp is an important element of the tooth since it provides nutrition, sensation, and defense against the various pathogens. Therefore, devitalized teeth are subsequent to various complications causing tooth strength reduction, increased fragility, and predisposition to postoperative fracture [47]. In terms of aesthetics, endodontic treatment often results in tooth crown discoloration due to either the filling material or the unsuccessful pulp chamber cleaning [48]. Thus, it becomes obvious that the maintaining of dental pulp vitality is of prime importance and this is highlighted by the emergence of new cell-based techniques focusing on partial or total pulp regeneration.

Missing teeth have traditionally been replaced with removable dentures , fixed bridges , and dental implants [49]. Currently, dental implants offer the most valuable option for tooth replacement, but a prerequisite for successful implant treatment is the quantity and quality of the remaining alveolar bone. Indeed, dental implant retention requires the close contact between the alveolar bone and the surface of the implant, a process called osseointegration . Dental implants are made of biocompatible titanium and they are inserted into the bone after surgical intervention. Survival rates of osseointegrated dental implants have been reported to be of over 95 % [50]. Apart alveolar bone quality and dimensions, the clinical success of implants also depends on primary implant stability, surgical methods, time of loading, infections, and implant surface characteristics [51]. When the dental implant is not well anchored to the bone, soft tissue encapsulation can occur, thus leading to unsuccessful treatment. Nanotechnology offer the opportunity to develop new implant surfaces that increased implant osseointegration [52], thus allowing the shortening of healing period without jeopardizing implant success [49]. However, the risk of infection of the tissues surrounding the implant (i.e., peri-implantitis) is still high and has to be taken seriously into account [53].

Recently, dental implants have been benefited from outcomes from stem cell biology and tissue engineering in order to maximize their survival rate in cases of poor bone quality. New regenerative technologies using scaffolds, stem cells, drug and growth factor delivery, and gene therapy are expected to enhance host tissue response and implant osseointegration [54]. Indeed, numerous pre-clinical studies have been performed already in various large animal models for guided bone regeneration around implants using growth factors and protein delivery [55, 56]. More recently, clinical studies have been realized using growth factor delivery for osseous and periodontal regeneration [57–59]. Pre-clinical applications for oral tissue regeneration using stem cell and gene therapies have been realized in rat models [60, 61]. Presently, safe and effective cell-based regenerative therapies have started to be applied in the dental clinics [54]. Clinical trials have documented that stem cells seeded in specific scaffolds are capable of generating sufficient amounts of bone in order to achieve primary implant stability [62–66]. However, all these new approaches should be further studied using controlled randomized clinical trials .

Novel cell-based therapeutic approaches have been proposed the last two decades [34, 67–69]. These treatments are promising, challenging, and complement traditional restorative or surgical techniques that are currently used in dentistry. The administration to patients of stem cells in conjunction with scaffolds and bioactive molecules might accelerate and increase the repair process of the impaired dental tissues. Although most of the studies focus on partial dental tissue regeneration, few attempts have been also made for the regeneration of entire teeth.

Here we report on selected dental stem cell populations that are currently used for experimental regenerative purposes in dentistry.

Stem cells play a critical role in tissue homeostasis and repair . Their fate is regulated by cell intrinsic determinants and signals from a specialized microenvironment [70–73]. Molecules of the Wnt, Notch, and BMP pathways have been shown to control stem cell fate specification [71, 74, 75]. The growing interest in the molecular regulation of dental stem cells arises from the potential to influence their fate and consequently their functions during tooth repair.

A considerable effort has been produced the last years to isolate epithelial and mesenchymal stem cell populations from deciduous and adult human teeth. Dental mesenchymal stem cells (DMSCs) were found in the dental pulp of permanent and exfoliated deciduous human teeth (Fig. 2) [11, 34, 69]. DMSCs were also identified in the apical part of dental papilla, the dental follicle, and the periodontal ligament. Because dental epithelial stem cells (DESCs) are very rare in adult human teeth, the current knowledge on DESCs has been obtained from studies in rodent incisors, which are continuously growing teeth [24, 76].